Persons living with HIV (PLWH) continuously experience symptom burdens. Their symptom prevalence and severity are also quite different. Mobile health (mHealth) applications (apps) offer exceptional opportunities for using personalized interventions when and where PLWH are needed. This study aimed to demonstrate the development process of the symptom management (SM) app and the structure and content of it. Our research team systematically searched for evidence-based resources and summarized up-to-date evidence for symptom management and health education. Our multidisciplinary research team that included physicians, nurses, software engineers, and nursing professors, evaluated the structure and content of the drafted app. Both quantitative data and qualitative results were collected at a group discussion meeting. Quantitative data were scores of sufficient evidence, situational suitability, practicability, cost-effectiveness, and understandability (ranged from one to four) for 119 items of the app contents, including the health tracking module, the self-assessment module, coping strategies for 18 symptoms (80 items), medication management, complementary therapy, diet management, exercise, relaxation techniques, and the obtaining support module. The SM app was comprised of eight modules and provided several personalized symptom management functions, including assessing symptoms and receiving different symptom management strategies, tracking health indicators, and communicating with medical staff. The SM app was a promising and flexible tool for HIV symptom management. It provided PLWH with personalized symptom management strategies and facilitated the case management for medical staff. Future studies are needed to further test the app’s usability among PLWH users and its effects on symptom management.